Egfr inhibitor free base or acid salt polycrystalline form, preparation method therefor, and application

ABSTRACT

Disclosed are an EGFR inhibitor free base or acid salt polycrystalline form, a preparation method therefor, and an application thereof. The present invention specifically relates to an N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide free base or acid salt polycrystalline form, a preparation method therefor, and an application of the polycrystalline form in preparing a drug for treating an EGFR mutant activity-mediated disease. The present invention is used for inhibiting the activity of an L858R EGFR mutant, a T790M EGFR mutant and an exon 19 deletion activating mutant etc., may be widely applied in preventing and treating cancer, especially non-small cell lung cancer and other related diseases, and is expected to develop into a new generation of EGFR inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/085,117 filed Sep. 14, 2018, allowed Apr. 29, 2020, which is aSection 371 of International Application No. PCT/CN2016/111717, filedDec. 23, 2016, which was published in the Chinese language on Sep. 28,2017, under International Publication No. WO 2017/161937 A1, whichclaims priority under 35 U.S.C. § 119(b) to Chinese Application No.201610165018.6, filed Mar. 22, 2016, the disclosures of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention belongs to the technical field of drugdevelopment, and specifically relates to a free base or acid saltpolymorph of an EGFR inhibitor, a preparation method, and applicationthereof.

BACKGROUND OF THE INVENTION

EGFR (epidermal growth factor receptor) is a member of the erbB receptorfamily, which includes transmembrane protein tyrosine kinase receptors.By binding to its ligand, such as epidermal growth factor (EGF), EGFRcan form a homodimer on the cell membrane or form a heterodimer withother receptors in the family, such as erbB2, erbB3, or erbB4. Theformation of these dimers can cause the phosphorylation of key tyrosineresidues in EGFR cells, thereby activating a number of downstreamsignaling pathways in cells. These intracellular signaling pathways playan important role in cell proliferation, survival and anti-apoptosis.Disorders of EGFR signal transduction pathways, including increasedexpression of ligands or receptors, EGFR gene amplification and mutationand the like, can promote malignant transformation of cells, and play animportant role in tumor cell proliferation, or invasion, metastasis andangiogenesis. Therefore, EGFR is a reasonable target for the developmentof anticancer drugs.

Therefore, Jiangsu Hansoh Pharmaceutical Group Co., Ltd. developed asmall molecule EGFR inhibitor in the patent applicationPCT/CN2015/091189 (a compound of formula I, the chemical name is:N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide),which has the following structure:

This small molecule EGFR inhibitor has high selectivity for inhibitingthe EGFR T790M mutant, and has no or low activity to wild-type EGFR. Dueto this high selectivity, the skin and gastrointestinal damage caused byinhibition of wild-type EGFR can be greatly reduced, and thedrug-resistant tumor caused by the secondary mutation of EGFR-T790M canbe treated. In addition, it makes sense to maintain the inhibitoryactivity to EGFR-activated mutant (including EGFR-L858R and delE746_A750with exon 19 deletion). Due to the higher selectivity and safety of thissmall molecule EGFR inhibitor, it is expected to be developed into aclinical first-line therapeutic drug.

DESCRIPTION OF THE INVENTION

In order to solve the technical problems in the prior art, the inventorshave intensively studied the different aggregation states of the freebase or acid salt of the compound of formula I to obtain a number of thefree base or acid salt polymorphs of the compound of formula I, whichcan greatly improve the physical and chemical properties of theamorphous form of the compound of formula I, such as crystallinity,solubility, hygroscopicity and chemical stability, and the processoperability is improved, thereby screening out pharmaceuticallyacceptable, the most suitable aggregation state, and providingscientific basis for drug development.

In the first aspect, the present invention provides a free base or acidsalt polymorph of the compound of formula I, i.e.,N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide.

In a preferred embodiment, the acid salt comprises an inorganic acidsalt or an organic acid salt.

In a further preferred embodiment, the inorganic acid salt is selectedfrom the group consisting of hydrochloride, sulfate, hydrobromide,hydrofluoride, hydroiode and phosphate; preferably, the inorganic acidsalt is selected from the group consisting of hydrochloride, sulfate andphosphate.

In a further preferred embodiment, the organic acid salt is selectedfrom the group consisting of acetate, propionate, hexanoate, caprylate,fumarate, maleate, malonate, succinate, glutarate, adipate, sebacate,dichloroacetate, trichloroacetate, acetohydroxamate, salicylate,4-aminosalicylate, benzoate, 4-acetylaminobenzoate, 4-aminobenzoate,caprate, cinnamate, citrate, aspartate, camphorate, gluconate,glucuronate, glutamate, erythorbate, lactate, aspartate, malate,mandelate, pyroglutamate, tartrate, lauryl sulfate, dibenzoyltartrate,2,5-dihydroxybenzoate, 1-hydroxy-2-naphthoate, mesylate,ethyl-1,2-disulfonate, ethanesulfonate, benzenesulfonate,4-chlorobenzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate,camphorsulfonate, 1,5-naphthalenedisulfonate, naphthalene-2-sulfonate,formate, galactonate, gentisate, 2-ketoglutarate, glycolate, hippurate,isethionate, lactobionate, ascorbate, aspartate, laurate, camphorate,nicotinate, oleate, orotate, oxalate, palmitate, pamoate, stearate,thiocyanate, undecylenate, trifluoroacetate and succinate, preferably,the organic acid salt is selected from the group consisting of mesylate,fumarate, maleate and acetate.

In a still further preferred embodiment, the present invention providesa free base polymorph of the compound of formula I. The free basepolymorph comprises three crystal forms, referred to as crystal form I,crystal form II and crystal form III of the free base, respectively.

The present invention provides a crystal form I of the free base of thecompound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 24.4±0.2°, 15.1±0.2°,25.2±0.2° and 7.4±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 23.1±0.2°, 19.6±0.2°, 14.1±0.2°,16.7±0.2° and 11.4±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 24.9±0.2°, 20.6±0.2°, 22.7±0.2°,9.7±0.2°, 26.1±0.2° and 21.8±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal form Iof the free base of the compound of formula I according to the presentinvention comprises substantially the same peaks at diffraction angles(2θ) as shown in FIG. 1, and the X-ray powder diffraction data are shownin Table 1:

TABLE 1 2θ (°) intensity % 7.4 55.2 9.7 15.8 10.8 11.2 11.4 28.8 14.138.4 15.1 65.5 15.5 9.0 16.7 37.2 17.8 7.5 18.5 10.3 19.6 39.9 20.6 23.921.8 11.5 22.7 16.8 23.1 44.2 24.4 100.0 24.9 25.6 25.2 58.3 26.1 14.730.4 10.9

The present invention provides a crystal form II of the free base of thecompound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 18.9±0.2°, 25.9±0.2°,31.6±0.2° and 21.0±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 15.0±0.2°, 16.1±0.2°, 24.4±0.2°,19.1±0.2° and 8.7±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 8.4±0.2°, 10.4±0.2°, 22.0±0.2°,17.7±0.2°, 22.5±0.2° and 26.4±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal formII of the free base of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (20) as shown in FIG. 2, and the X-ray powder diffraction dataare shown in Table 2:

TABLE 2 2θ (°) intensity % 8.4 41.4 8.7 47.3 9.5 19.6 10.4 40.1 15.058.7 16.1 57.6 17.7 37.9 18.6 21.4 18.9 100.0 19.1 47.6 20.2° 25.0 21.085.5 22.0 39.8 22.5 37.5 23.5 21.7 24.4 54.7 25.5 20.1 25.9 95.9 26.428.8 31.6 94.3

The present invention provides a crystal form III of the free base ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 8.0±0.2°, 23.7±0.2°,19.0±0.2° and 18.6±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 23.9±0.2°, 16.1±0.2°, 22.5±0.2°,22.1±0.2° and 11.1±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 10.4±0.2°, 14.1±0.2°, 15.7±0.2°,12.1±0.2°, 8.7±0.2° and 28.9±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal formIII of the free base of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 3, and the X-ray powder diffraction dataare shown in Table 3:

TABLE 3 2θ (°) intensity % 8.0 100.0 23.7 64.7 19.0 42.9 18.6 37.4 23.936.4 16.1 28.8 22.5 18.8 22.1 16.0 11.1 14.7 10.4 13.7 14.1 13.3 15.713.1 12.1 10.8 8.7 9.3 28.9 8.6 18.0 6.9 28.4 6.2 14.7 5.4 16.9 5.3 26.54.5

In a still further preferred embodiment, the present invention providesa crystal form I of a hydrochloride salt of the compound of formula Ihaving an X-ray powder diffraction spectrum comprising peaks atdiffraction angles (2θ) of 24.0±0.2°, 6.6±0.2°, 8.8±0.2° and 25.8±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 14.2±0.2°, 21.6±0.2°, 6.9±0.2°,25.2±0.2° and 27.0±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 22.7±0.2°, 12.7±0.2°, 6.4±0.2°,20.2±0.2°, 17.8±0.2° and 11.0±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal form Iof the hydrochloride salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 4, and the X-ray powder diffraction dataare shown in Table 4:

TABLE 4 2θ (°) intensity % 6.4 36.5 6.6 75.6 6.9 47.0 8.8 74.4 11.0 31.712.3 27.2 12.7 36.7 13.3 27.6 14.2 53.9 17.8 31.9 18.0 31.0 20.2 32.521.6 51.9 22.7 37.4 24.0 100.0 25.2 39.7 25.8 68.7 26.8 24.2 27.0 39.028.2 25.0

In a still further preferred embodiment, the present invention providesa sulfate salt polymorph of the compound of formula I in polycrystallineform. The sulfate salt polymorph comprises four crystal forms, referredto as crystal form I, crystal form II, crystal form III and crystal formIV, respectively.

The present invention provides a crystal form I of the sulfate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 16.3±0.2°, 11.9±0.2°,13.7±0.2° and 22.3±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 24.3±0.2°, 19.6±0.2°, 24.9±0.2°,20.7±0.2° and 18.8±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 24.0±0.2°, 8.5±0.2°, 10.5±0.2°,17.8±0.2°, 21.9±0.2° and 22.8±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal form Iof the sulfate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 5, and the X-ray powder diffraction dataare shown in Table 5:

TABLE 5 2θ (°) intensity % 8.5 44.3 8.8 26.7 10.5 44.1 11.9 90.9 13.776.6 15.6 31.4 16.3 100.0 17.2 30.4 17.8 43.4 18.8 51.0 19.6 57.6 20.751.6 21.9 42.5 22.3 74.2 22.8 36.1 24.0 49.6 24.3 72.4 24.9 53.1 25.632.9 29.4 29.1

The present invention provides a crystal form II of the sulfate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 10.7±0.2°, 22.5±0.2°,25.8±0.2° and 9.3±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 21.6±0.2°, 15.8±0.2°, 19.9±0.2°,18.9±0.2° and 22.2±0.2.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 14.0±0.2°, 27.9±0.2°, 11.5±0.2°,23.0±0.2°, 31.7±0.2° and 24.0±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal formII of the sulfate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 6, and the X-ray powder diffraction dataare shown in Table 6:

TABLE 6 2θ (°) intensity % 7.2 19.1 7.6 21.0 9.3 78.1 10.7 100.0 11.534.0 14.0 36.4 15.2 18.8 15.8 58.9 18.9 48.7 19.9 55.5 20.6 22.1 21.669.0 22.2 39.0 22.5 96.5 23.0 28.6 23.4 19.2 24.0 23.6 25.8 90.3 27.934.2 31.7 27.1

The present invention provides a crystal form III of the sulfate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 22.1±0.2°, 23.6±0.2°,10.4±0.2° and 21.6±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 24.0±0.2°, 12.7±0.2°, 8.0±0.2°,25.7±0.2° and 14.6±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 17.1±0.2°, 20.9±0.2°, 27.0±0.2°,11.0±0.2°, 18.2±0.2° and 16.5±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal formIII of the sulfate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 7, and the X-ray powder diffraction dataare shown in Table 7:

TABLE 7 2θ (°) intensity % 7.4 13.4 8.0 38.4 9.0 10.9 10.4 90.0 11.021.2 12.7 41.2 14.6 32.3 15.2 13.6 16.5 16.9 17.1 30.4 18.2 17.9 19.213.7 20.9 25.6 21.6 83.6 22.1 100.0 23.6 97.7 24.0 81.3 25.7 33.2 27.023.9 29.4 16.7

The present invention provides a crystal form IV of the sulfate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 20.0±0.2°, 6.8±0.2°,9.3±0.2° and 23.2±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 25.2±0.2°, 22.5±0.2°, 17.7±0.2°,20.5±0.2° and 14.9±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 14.4±0.2°, 24.2±0.2°, 17.4±0.2°,26.3±0.2°, 16.9±0.2° and 14.2±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal formIV of the sulfate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 8, and the X-ray powder diffraction dataare shown in Table 8:

TABLE 8 2θ (°) intensity % 6.8 92.7 9.3 74.4 14.2 32.6 14.4 48.9 14.951.2 16.2 25.5 16.9 33.1 17.4 43.4 17.7 59.3 18.2 23.1 20.0 100.0 20.552.1 22.5 59.6 23.2 63.6 24.2 45.4 25.2 59.9 25.5 27.3 26.3 37.9 28.026.8 30.2 23.3

In a still further preferred embodiment, the present invention providesa crystal form I of a phosphate salt of the compound of formula I havingan X-ray powder diffraction spectrum comprising peaks at diffractionangles (2θ) of 22.6±0.2°, 10.7±0.2°, 21.6±0.2° and 17.8±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 24.4±0.2°, 13.3±0.2°, 15.3±0.2°,12.8±0.2° and 20.1±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 14.4±0.2°, 20.6±0.2°, 25.4±0.2°,19.2±0.2°, 10.1±0.2° and 12.3±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal form Iof the phosphate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 9, and the X-ray powder diffraction dataare shown in Table 9:

TABLE 9 2θ (°) intensity % 10.1 19.8 10.7 80.4 12.0 14.1 12.3 19.6 12.826.5 13.3 31.6 14.4 24.0 15.3 28.0 15.6 18.6 16.7 18.0 17.8 56.2 19.219.9 20.1 26.0 20.6 22.3 21.6 56.8 22.6 100.0 23.4 18.3 24.4 40.7 25.420.0 26.3 13.1

In a still further preferred embodiment, the present invention providesa mesylate salt polymorph of the compound of formula I. The mesylatesalt polymorph comprises six crystal forms, referred to as crystal formI, crystal form II, crystal form III, crystal form IV, crystal form Vand crystal form VI of the mesylate salt, respectively.

The present invention provides a crystal form I of the mesylate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 19.1±0.2°, 25.6±0.2°,15.0±0.2° and 25.0±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 20.5±0.2°, 10.2±0.2°, 19.7±0.2°,24.4±0.2° and 23.0±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 9.4±0.2°, 16.3±0.2°, 17.4±0.2°,8.6±0.2°, 21.2±0.2° and 22.6±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal form Iof the mesylate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 10, and the X-ray powder diffraction dataare shown in Table 10:

TABLE 10 2θ (°) intensity % 6.8 19.6 8.6 29.9 9.4 43.1 10.2 59.9 15.075.7 16.3 41.1 16.9 24.0 17.4 30.7 17.9 22.3 19.1 100.0 19.7 58.6 20.566.8 21.2 28.2 22.6 26.5 23.0 48.6 24.4 52.9 25.0 68.8 25.6 79.3 27.620.9 32.4 20.7

The present invention provides a crystal form II of the mesylate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 24.3±0.2°, 20.1±0.2°,11.0±0.2° and 20.6±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 17.4±0.2°, 22.7±0.2°, 23.8±0.2°,12.1±0.2° and 15.7±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 8.7±0.2°, 16.7±0.2°, 15.1±0.2,18.5±0.2°, 17.7±0.2° and 6.5±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal formII of the mesylate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 11, and the X-ray powder diffraction dataare shown in Table 11:

TABLE 11 2θ (°) intensity % 6.5 11.6 7.0 10.2 8.7 22.9 11.0 41.4 12.125.2 12.7 7.6 15.1 21.4 15.7 23.2 16.7 22.6 17.4 39.4 17.7 15.7 18.519.9 20.1 52.0 20.6 39.5 22.7 38.1 23.8 37.3 24.3 100.0 26.8 7.5 32.88.2 40.6 9.5

The present invention provides a crystal form III of the mesylate saltof the compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 24.5±0.2°, 22.6±0.2°,6.1±0.2° and 18.8±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 15.7±0.2°, 11.7±0.2°, 21.3±0.2°,23.8±0.2° and 8.4±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 16.7±0.2°, 17.3±0.2°, 9.4±0.2°,15.3±0.2°, 22.0±0.2° and 12.2±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal formIII of the mesylate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 12, and the X-ray powder diffraction dataare shown in Table 12:

TABLE 12 2θ (°) intensity % 6.1 68.4 8.4 27.4 9.4 24.8 11.7 50.3 12.217.9 13.7 14.8 15.3 22.8 15.7 50.5 16.7 25.1 17.3 25.1 18.4 12.2 18.850.9 21.3 44.0 22.0 18.8 22.6 77.7 23.8 30.1 24.5 100.0 27.2 14.6 28.715.5 30.3 12.1

The present invention provides a crystal form IV of the mesylate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 21.0±0.2°, 18.0±0.2°,25.1±0.2° and 13.6±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 21.4±0.2°, 22.6±0.2°, 19.9±0.2°,19.1±0.2° and 10.4±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 30.4±0.2°, 33.5±0.2°, 12.4±0.2°,31.7±0.2°, 17.5±0.2° and 8.3±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal formIV of the mesylate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 13, and the X-ray powder diffraction dataare shown in Table 13:

TABLE 13 2θ (°) intensity % 8.3 29.1 10.4 44.2 12.4 31.0 13.6 68.6 16.827.6 17.5 29.8 18.0 91.9 19.1 46.6 19.9 51.9 21.0 100.0 21.4 65.6 22.663.3 23.9 24.8 25.1 77.1 25.5 24.4 30.4 36.5 31.7 30.7 33.5 34.9 34.227.4 37.0 27.7

The present invention provides a crystal form V of the mesylate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 24.6±0.2°, 23.3±0.2°,14.9±0.2° and 20.1±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 22.9±0.2°, 10.9±0.2°, 17.0±0.2°,25.7±0.2° and 13.9±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 15.3±0.2°, 27.0±0.2°, 30.5±0.2°,18.7±0.2°, 20.6±0.2° and 21.9±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal form Vof the mesylate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 14, and the X-ray powder diffraction dataare shown in Table 14:

TABLE 14 2θ (°) intensity % 8.4 15.0 9.4 20.6 10.9 51.1 13.9 41.0 14.958.2 15.3 27.9 15.9 14.1 17.0 45.1 18.7 25.0 20.1 53.8 20.6 23.3 21.922.2 22.9 52.5 23.3 78.9 24.6 100.0 25.7 44.0 27.0 26.9 30.5 26.9 39.322.0 39.8 17.4

The present invention provides a crystal form VI of the mesylate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 11.7±0.2°, 19.8±0.2°,17.2±0.2° and 6.8±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 23.6±0.2°, 22.6±0.2°, 25.5±0.2°,24.2±0.2° and 23.2±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 18.9±0.2°, 18.6±0.2°, 22.4±0.2°,14.1±0.2°, 24.6±0.2° and 10.9±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal formVI of the mesylate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 15, and the X-ray powder diffraction dataare shown in Table 15:

TABLE 15 2θ (°) intensity % 6.8 63.4 7.9 23.2 8.7 34.0 10.9 34.1 11.7100.0 12.6 34.0 14.1 38.3 17.2 80.9 17.8 26.7 18.6 42.8 18.9 44.8 19.891.7 22.0 33.6 22.4 38.6 22.6 51.7 23.2 45.7 23.6 55.8 24.2 48.0 24.636.8 25.5 49.9

In a still further preferred embodiment, the present invention providesa fumarate salt polymorph of the compound of formula I. The fumaratesalt polymorph comprises two crystal forms, referred to as crystal formI and crystal form II of the fumarate salt, respectively.

The present invention provides a crystal form I of the fumarate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 7.1±0.2°, 12.0±0.2°,14.9±0.2° and 17.1±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 19.1±0.2°, 23.4±0.2°, 23.7±0.2°,26.6±0.2° and 28.7±0.2°.

More preferably, the X-ray powder diffraction spectrum furthercomprising peaks at diffraction angles (2θ) of 25.2±0.2°, 10.5±0.2°,25.6±0.2°, 38.7±0.2°, 13.3±0.2° and 7.8±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal form Iof the fumarate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 16, and the X-ray powder diffraction dataare shown in Table 16:

TABLE 16 2θ (°) intensity % 7.1 100.0 7.8 7.7 10.5 13.7 12.0 94.6 13.38.5 14.9 80.7 17.1 62.2 19.1 49.7 19.8 6.0 21.2 6.7 23.4 41.0 23.7 36.625.2 15.1 25.6 12.9 26.6 27.2 28.7 23.4 30.1 5.5 30.3 5.8 30.5 7.6 38.79.0

The present invention provides a crystal form II of the fumarate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 6.0±0.2°, 22.7±0.2°,25.1±0.2° and 23.3±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 16.9±0.2°, 25.5±0.2°, 24.2±0.2°,8.8±0.2° and 11.9±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 20.5±0.2°, 29.5±0.2°, 8.3±0.2°,19.9±0.2°, 13.7±0.2° and 37.6±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal formII of the fumarate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 17, and the X-ray powder diffraction dataare shown in Table 17:

TABLE 17 2θ (°) intensity % 6.0 100.0 8.3 21.9 8.8 50.2 11.9 49.0 13.719.8 14.3 17.7 16.9 56.7 17.7 18.2 18.2 13.6 19.9 20.2 20.5 34.4 21.615.2 22.7 75.3 23.3 58.9 24.2 54.5 25.1 59.6 25.5 56.4 29.5 25.9 34.513.5 37.6 18.6

In a still further preferred embodiment, the present invention providesa maleate salt polymorph of the compound of formula I. The maleate saltpolymorph comprises three crystal forms, referred to as crystal form I,crystal form II and crystal form III of the maleate salt, respectively.

The present invention provides a crystal form I of the maleate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 7.9±0.2°, 24.6±0.2°,7.5±0.2° and 18.2±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 7.2±0.2°, 22.5±0.2°, 14.5±0.2°,25.4±0.2° and 21.0±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 19.7±0.2°, 13.0±0.2°, 15.1±0.2°,19.1±0.2°, 22.0±0.2° and 11.7±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal form Iof the maleate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 18, and the X-ray powder diffraction dataare shown in Table 18:

TABLE 18 2θ (°) intensity % 7.2 69.5 7.5 88.8 7.9 100.0 11.7 26.4 13.031.9 14.1 26.0 14.5 56.2 15.1 30.2 15.9 25.7 18.2 71.5 19.1 27.3 19.739.5 21.0 45.4 22.0 26.6 22.5 61.6 23.3 24.5 23.6 22.7 24.6 97.6 25.454.5 27.2 24.8

The present invention provides a crystal form II of the maleate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 20.3±0.2°, 24.9±0.2°,23.4±0.2° and 16.8±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 7.2±0.2°, 18.6±0.2°, 21.0±0.2°,10.1±0.2° and 9.8±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 25.5±0.2°, 13.6±0.2°, 18.3±0.2°,12.5±0.2°, 21.6±0.2° and 15.4±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal formII of the maleate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 19, and the X-ray powder diffraction dataare shown in Table 19:

TABLE 19 2θ (°) intensity % 2θ (°) intensity % 7.2 43.4 18.6 38.3 9.827.5 20.3 100.0 10.1 31.6 21.0 38.1 12.5 21.3 21.6 21.3 12.9 9.9 22.512.0 13.6 24.5 23.4 55.6 15.4 19.5 24.9 56.0 15.9 11.5 25.5 27.0 16.844.5 26.7 11.2 18.3 21.5 27.2 13.0

The present invention provides a crystal form III of the maleate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 21.6±0.2°, 22.4±0.2°,17.9±0.2° and 25.8±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 7.7±0.2°, 23.4±0.2°, 24.4±0.2°,11.9±0.2° and 26.6±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 16.4±0.2°, 15.4±0.2°, 17.6±0.2°,12.4±0.2°, 19.7±0.2° and 21.2±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal formIII of the maleate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 20, and the X-ray powder diffraction dataare shown in Table 20:

TABLE 20 2θ (°) intensity % 7.7 73.4 11.9 47.4 12.4 34.8 14.7 27.4 15.442.7 16.4 43.5 16.8 26.9 17.6 36.6 17.9 82.5 19.7 33.3 21.2 32.9 21.6100.0 22.4 89.9 23.1 30.7 23.4 72.1 24.4 62.1 25.8 77.2 26.6 44.0 28.232.0 30.2 22.6

In a still further preferred embodiment, the present invention providesan acetate salt polymorph of the compound of formula I. The acetate saltpolymorph comprises two crystal forms, referred to as crystal form I andcrystal form II of the acetate salt, respectively.

The present invention provides a crystal form I of the acetate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 23.0±0.2°, 11.8±0.2°,16.3±0.2° and 7.4±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 22.5±0.2°, 13.0±0.2°, 14.9±0.2°,13.4±0.2° and 6.5±0.2°.

More preferably, the X-ray powder diffraction spectrum furthercomprising peaks at diffraction angles (2θ) of 29.3±0.2°, 12.4±0.2°,20.1±0.2°, 9.7±0.2°, 24.0±0.2° and 28.0±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal form Iof the acetate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 21, and the X-ray powder diffraction dataare shown in Table 21:

TABLE 21 2θ (°) intensity % 6.5 23.8 7.4 56.4 9.7 21.4 10.3 15.4 11.872.8 12.4 21.6 13.0 32.8 13.4 26.0 14.2 13.6 14.9 29.6 16.3 67.3 17.816.5 20.1 21.5 20.5 17.0 22.5 56.0 23.0 100.0 24.0 18.0 28.0 17.8 29.323.7

The present invention provides a crystal form II of the acetate salt ofthe compound of formula I having an X-ray powder diffraction spectrumcomprising peaks at diffraction angles (2θ) of 8.4±0.2°, 19.9±0.2°,23.0±0.2° and 24.8±0.2°.

Preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 24.4±0.2°, 16.9±0.2°, 13.9±0.2°,19.6±0.2° and 11.0±0.2°.

More preferably, the X-ray powder diffraction spectrum further comprisespeaks at diffraction angles (2θ) of 6.4±0.2°, 17.8±0.2°, 24.1±0.2°,9.7±0.2°, 11.9±0.2° and 26.6±0.2°.

Most preferably, the X-ray powder diffraction spectrum of crystal formII of the acetate salt of the compound of formula I according to thepresent invention comprises substantially the same peaks at diffractionangles (2θ) as shown in FIG. 22, and the X-ray powder diffraction dataare shown in Table 22:

TABLE 22 2θ (°) intensity % 6.4 35.2 8.4 100.0 9.7 25.4 11.0 37.3 11.921.1 13.9 41.4 16.9 45.9 17.8 34.3 18.8 17.7 19.6 40.3 19.9 68.4 20.813.6 22.0 16.0 23.0 64.3 23.7 14.8 24.1 26.7 24.4 50.9 24.8 57.1 26.618.9 30.4 18.3

The term “substantially the same” related to X-ray diffraction peakposition as used herein means to consider the typical peak position andintensity variability. For example, those skilled in the art willunderstand that the measured values of the peak positions (2θ) will bechanged due to the different XRPD instruments, and sometimes this changemay reach up to 0.2°. Moreover, those skilled in the art will understandthat the preparation method of the XRPD sample, the XRPD instruments,the crystallinity of the sample, the sample amount, the preferredorientation of the crystal and other factors will cause a change ofrelative peak intensity of the sample in the XRPD spectrum.

In another aspect, the present invention provides a method for preparingthe free base polymorph, the acid salt or the acid salt polymorph of thecompound of formula I. The method for preparing the free base polymorphis selected from the following preparation methods:

Method 1: step 1: dissolving the free base of the compound of formula Iin an aqueous solvent, an organic solvent or a mixed solvent; step 2:cooling the solution to precipitate the polymorph, or adding ananti-solvent to the clear solution of the compound to precipitate thepolymorph, or evaporating the clear solution of the compound slowly, oradding an original compound solid or other solid particle additive as aheteronuclear crystal seed to the solution of the compound to induce thepolymorph;

Method 2: dispersing the compound in an aqueous solvent, an organicsolvent or a mixed solvent, or in an atmosphere of these media to obtainthe polymorph; and

Method 3: combining method 1 and method 2 to obtain the free basepolymorph. The method for preparing the acid salt polymorph of thecompound of formula I comprises the following steps of:

Step 1: preparing the acid salt of the compound of formula I, thespecific steps being as follows: dissolving or dispersing the free baseof the compound in an aqueous solvent or a suitable organic solvent, andthen adding a liquid or solid or solution of inorganic acid or organicacid to the above system to prepare the acid salt of the compound offormula I; or, adding the free base solid to an acid solution to preparethe acid salt of the compound of formula I; and

Step 2: preparing the acid salt polymorph of the compound of formula Iin accordance with the above method for preparing the free basepolymorph.

In a further preferred embodiment, the organic solvent comprises, but isnot limited to, the solvents listed below, for example, methanol,ethanol, isopropanol, acetonitrile, acetone, ethyl acetate, isopropylacetate, toluene, n-butanol, cyclohexane, dichloromethane,dimethylformamide, dimethylacetamide, dimethyl sulfoxide, dioxane, ethylether, n-heptane, n-hexane, methyl ethyl ketone, isooctane, pentane,dipropanol, tetrahydrofuran, dimethyl tetrahydrofuran, trichloroethane,dimethylbenzene or a mixture thereof. Other solvents can besupercritical fluids, such as carbon dioxide liquids, ionic liquids,polymer solutions, and the like.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of the abovefree base or acid salt polymorph of the compound of formula I and apharmaceutically acceptable carrier.

In another aspect, the present invention provides a use of the abovefree base or acid salt polymorph of the compound of formula I, or theabove pharmaceutical composition in the preparation of a medicament fortreating a disease mediated by the activity of an EGFR mutant or theactivity of a mutant activated by exon 19 deletion.

Preferably, the EGFR mutant is selected from the group consisting ofEGFR-L858R mutant and EGFR-T790M.

More preferably, the disease mediated by the activity of an EGFR mutantcomprises a disease mediated alone or partially by the activity of anEGFR mutant.

In another aspect, the present invention provides a use of the abovefree base or acid salt polymorph of the compound of formula I, or theabove pharmaceutical composition in the preparation of a medicament fortreating cancer.

Preferably, the cancer is selected from the group consisting of ovariancancer, cervical cancer, colorectal cancer, breast cancer, pancreaticcancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia,lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer,hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor(GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renalcancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML),multiple myeloma, melanoma and mesothelioma.

More preferably, the cancer is non-small cell lung cancer.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is the X-ray powder diffraction spectrum of crystal form I of thefree base of the compound of formula I.

FIG. 2 is the X-ray powder diffraction spectrum of crystal form II ofthe free base of the compound of formula I.

FIG. 3 is the X-ray powder diffraction spectrum of crystal form III ofthe free base of the compound of formula I.

FIG. 4 is the X-ray powder diffraction spectrum of crystal form I of ahydrochloride salt of the compound of formula I.

FIG. 5 is the X-ray powder diffraction spectrum of crystal form I of asulfate salt of the compound of formula I.

FIG. 6 is the X-ray powder diffraction spectrum of crystal form II of asulfate salt of the compound of formula I.

FIG. 7 is the X-ray powder diffraction spectrum of crystal form III of asulfate salt of the compound of formula I.

FIG. 8 is the X-ray powder diffraction spectrum of crystal form IV of asulfate salt of the compound of formula I.

FIG. 9 is the X-ray powder diffraction spectrum of crystal form I of aphosphate salt of the compound of formula I.

FIG. 10 is the X-ray powder diffraction spectrum of crystal form I of amesylate salt of the compound of formula I.

FIG. 11 is the X-ray powder diffraction spectrum of crystal form II of amesylate salt of the compound of formula I.

FIG. 12 is the X-ray powder diffraction spectrum of crystal form III ofa mesylate salt of the compound of formula I.

FIG. 13 is the X-ray powder diffraction spectrum of crystal form IV of amesylate salt of the compound of formula I.

FIG. 14 is the X-ray powder diffraction spectrum of crystal form V of amesylate salt of the compound of formula I.

FIG. 15 is the X-ray powder diffraction spectrum of crystal form VI of amesylate salt of the compound of formula I.

FIG. 16 is the X-ray powder diffraction spectrum of crystal form I of afumarate salt of the compound of formula I.

FIG. 17 is the X-ray powder diffraction spectrum of crystal form II of afumarate salt of the compound of formula I.

FIG. 18 is the X-ray powder diffraction spectrum of crystal form I of amaleate salt of the compound of formula I.

FIG. 19 is the X-ray powder diffraction spectrum of crystal form II of amaleate salt of the compound of formula I.

FIG. 20 is the X-ray powder diffraction spectrum of crystal form III ofa maleate salt of the compound of formula I.

FIG. 21 is the X-ray powder diffraction spectrum of crystal form I of anacetate salt of the compound of formula I.

FIG. 22 is the X-ray powder diffraction spectrum of crystal form II ofan acetate salt of the compound of formula I.

PREFERRED EMBODIMENTS

1. Terms

The term “pharmaceutically acceptable” as used herein refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animal without excessive toxicity,irritation, allergic reaction or other problematic complications, andare commensurate with a reasonable benefit to risk ratio.

The term “substantially pure” as used herein refers to, in certainpreferred embodiments of the present invention, the crystallinestructure of the compound of formula I being in substantially pure form,i.e., the HPLC purity or crystal form is substantially above 90%(including the number itself), preferably above 95%, more preferablyabove 98%, and most preferably above 99.5%.

The term “polymorphism” or “polymorph” as used herein refers to crystalforms having the same chemical composition but different spatialarrangement of the molecules, atoms, and/or ions forming the crystal.Although polymorphs have the same chemical composition, they differ inpacking and geometric arrangement, and can exhibit different physicalproperties, such as melting point, shape, color, density, hardness,deformability, stability, solubility, dissolution rate and similarproperties. Depending on their temperature-stability relationship, twopolymorphs can be either monotropic or enantiotropic. For a monotropicsystem, the relative stability between the two solid phases remainsconstant as the temperature changes. In contrast, in an enantiotropicsystem, there is a transition temperature at which the stability of thetwo phases is reversed (Theory and Origin of Polymorphism in“Polymorphism in Pharmaceutical Solids” (1999) ISBN: )-8247-0237). Thephenomenon of a compound existing in different crystal structures iscalled drug polymorphism phenomenon.

The crystalline structures of the present invention can be prepared byvarious methods, including crystallization or recrystallization from asuitable solvent, sublimation, growth from a melt, solid statetransformation from another phase, crystallization from a supercriticalfluid, jet spray, and the like. Techniques for crystallization orrecrystallization of crystalline structures from a solvent mixtureinclude solvent evaporation, decreasing the temperature of the solventmixture, seeding in a supersaturated solvent mixture of the moleculeand/or salt thereof, lyophilizing the solvent mixture, or adding ananti-solvent to the solvent mixture, and the like. Crystallinestructures, including polymorphs, can be prepared using high-throughputcrystallization techniques. Drug crystals including polymorphs, methodsof preparation and characterization of drug crystals are disclosed inSolid-State Chemistry of Drugs, S. R. Byrn, R. R. Pfeiffer, and J. G.Stowell, 2nd, SSCI, West Lafayette, Ind., 1999.

In addition, as known to those skilled in the art, seed crystals areadded to any crystallization mixture to promote crystallization. Thus,the present invention can also use seed crystals as a means ofcontrolling the growth of a particular crystalline structure or as ameans of controlling the particle size distribution of the crystallineproduct. Accordingly, as described in “Programmed cooling of batchcrystallizers,” J. W. Mullin and J. Nyvlt, Chemical Engineering Science,1971, 26, 369-377, the calculation of the amount of seed crystalrequired depends on the size of the available seed crystal and thedesired size of the average product particle. In general, small sizedspecies are needed to effectively control the growth of crystals in thebatch. Small sized seed crystals can be produced by sieving, milling, ormicronizing of larger crystals, or by solution micro-crystallization. Itshould be noted that the milling or micronizing of the crystals cannotresult in any change in the crystallinity of the desired crystalstructure (i.e., change to amorphous or to another polymorph).

Crystal structures equivalent to the crystal structures disclosed orclaimed in the present invention can exhibit similar but not identicalanalytical properties within a reasonable error range, depending on testconditions, purity, equipment, and other common variables known to thoseskilled in the art. Accordingly, it will be apparent to those skilled inthe art that various modifications and variations can be made in thepresent invention without departing from the scope or spirit of thepresent invention. Other embodiments of the present invention will beapparent to those skilled in the art from consideration of thespecification of the present invention disclosed herein and based onpractice. Applicants intend that the specification and examples beconsidered as exemplary, but not as limiting the scope thereof.

As used herein, the term “room temperature” or “RT” refers to an ambienttemperature of 20 to 25° C. (68-77° F.).

2. Experimental Materials

The reagents used in the examples of the present invention arecommercially available industrial grade or analytical grade reagents.The selected compound of formula I is an amorphous solid which isprepared according to Example 26 of Patent Application PCT/CN2015/091189filed by Hansoh.

3. Analytical Method

3.1 X-Ray Powder Diffraction

Those skilled in the art will recognize that an X-ray powder diffractionpattern can be obtained with a measurement error that depends on themeasurement conditions used. In particular, it is generally known thatthe intensity in an X-ray powder diffraction pattern can fluctuatedepending on the material conditions used. It should be furtherunderstood that the relative intensity can also vary depending onexperimental conditions, and accordingly, the exact intensity should notbe taken into account. In addition, a measurement error of aconventional X-ray powder diffraction angle is usually about 5% or less,and such degree of measurement error should be regarded as belonging tothe diffraction angle described above. Therefore, it is to be understoodthat the crystal structures of the present invention are not limited tothe crystal structures that provide X-ray diffraction spectra exactlythe same as the X-ray powder diffraction spectra depicted in the Figuresdisclosed herein. Any crystal structures that provide X-ray powderdiffraction spectra substantially the same as those disclosed in theFigures fall within the scope of the present invention. The ability todetermine substantially the same X-ray powder diffraction spectra iswithin the ability of those skilled in the art. Other suitable standardcalibrations are known to those skilled in the art. However, therelative intensity can vary depending on the size and shape of thecrystal.

The polymorphs of the compound of formula I were characterized by theirX-ray powder diffraction (XRPD) spectra. Therefore, the X-ray powderdiffraction spectrum was collected by a Rigaku Uitimalv X-ray powderdiffractometer using Cu Kα radiation (1.54 Å) in reflective mode. Tubevoltage and current amount were set to 40 kV and 40 mA respectively. Inthe 2θ range of 5.0° to 45°, the sample was scanned for 5 minutes. Allanalysis was usually implemented at room temperature of 20° C.-30° C.The XRPD sample was prepared as follows: The sample was placed on amonocrystalline silicon wafer, then the sample powder was pressed by aglass sheet or an equivalent to ensure that the surface of the samplewas flat and had a suitable height. Then, the sample holder was placedin the Rigaku Uitimalv instrument, and the X-ray powder diffractionspectrum was collected using the above instrument parameters. Themeasured difference related to the analysis result of the X-ray powderdiffraction was produced by various factors including: (a) error insample preparation (e.g., sample height), (b) the instrument error, (c)the calibration error, (d) operator error (including those errors thatoccur in the determination of peak positions), and (e) properties of thesubstance (e.g. preferred orientation error). Calibration error andsample height error often lead to shifts of all the peaks in the samedirection. In general, the calibration factor will make the measuredpeak positions inconsistent with the expected peak positions and in therange of 2θ expected values ±0.2°.

Angle 2θ values (°) and intensity values (% relative to the highest peakvalue) of each polymorph obtained in the Examples of the presentinvention are shown in Tables 1 to 22.

3.2 Thermogravimetric Analysis (TGA)

Thermogravimetric analysis (TGA) experiments were performed on a TAInstruments™ model Q500. The sample (about 2-10 mg) was placed on apre-weighed platinum pan. The sample weight was accurately measured bythe instrument and recorded to a thousand of a milligram. The furnacewas purged with nitrogen at 100 ml/min. Data were collected between roomtemperature and 300° C. at a heating rate of 10° C./min.

3.3. Differential Scanning Calorimetry (DSC)

Differential Scanning calorimetry (DSC) experiments were performed on aTA Instruments™ model Q200. The sample (about 2-10 mg) was weighed in analuminum pan and accurately recorded to a hundred of a milligram andtransferred to the DSC. The instrument was purged with nitrogen at 50ml/min. Data were collected between room temperature to 300° C. at aheating rate of 10° C./min. The spectra were plotted when theendothermic peaks were downward. However, those skilled in the art willnotice that in the DSC measurement, the measured start temperature andthe maximum temperature vary in a certain degree, depending on theheating rate, crystal shape and purity, and other measured parameters.

The following specific examples are used to further describe theparticular aspects of the solutions of the invention, but these examplesare not intended to limit the scope of the invention in any way.

Example 1: Preparation of Crystal Form I of the Free Base of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, 100 μL of propanolas a positive solvent was added at each step, the mixture was shakenvertically and sonicated until the solid was completely dissolved, andthen the addition of the positive solvent was stopped. Under stirringcondition, water as an anti-solvent was slowly added at room temperatureuntil a large amount of solid precipitated. After the precipitationstopped, stirring was continued for twenty minutes. A solid-liquidseparation was carried out to obtain crystal form I of the free base ofthe compound of formual I. The X-ray powder diffraction spectrum isshown in FIG. 1.

Example 2: Preparation of Crystal Form II of the Free Base of theCompound of Formula I

About 20 mg of the free base solid of the compound I of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then ethylformate as a positive solvent was added. The mixture was shakenvertically, the solid was dissolved first and then quicklyrecrystallized to form a solid. A solid-liquid separation was carriedout to obtain crystal form II of the free base of the compound offormual I. The X-ray powder diffraction spectrum is shown in FIG. 2.

Example 3: Preparation of Crystal Form III of the Free Base of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, 100 μL of methanolas a positive solvent was added at each step, the mixture was shakenvertically and sonicated until the solid was completely dissolved, andthen the addition of the positive solvent was stopped. Under stirringconditions, water as an anti-solvent was slowly added at roomtemperature until a large amount of solid precipitated. After theprecipitation stopped, stirring was continued for twenty minutes. Asolid-liquid separation was carried out to obtain crystal form III ofthe free base of the compound of formual I. The X-ray powder diffractionspectrum is shown in FIG. 3.

Example 4: Preparation of Crystal Form I of a Hydrochloride Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofacetonitrile as a positive solvent was added to dissolve the solid.Under stirring conditions, an equimolar amount of hydrochloric acid wasadded to the vial at room temperature. After stirring was continued for24 hours, a solid-liquid separation was carried out to obtain crystalform I of the hydrochloride salt of the compound of formula I. The X-raypowder diffraction spectrum is shown in FIG. 4.

Example 5: Preparation of Crystal Form I of a Sulfate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofmethanol as a positive solvent were added to dissolve the solid. Understirring conditions, an equimolar amount of sulfuric acid was added tothe vial at room temperature. After stirring was continued for 24 hours,a solid-liquid separation was carried out to obtain crystal form I ofthe sulfate salt of the compound of formula I. The X-ray powderdiffraction spectrum is shown in FIG. 5.

Example 6: Preparation of Crystal Form II of a Sulfate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofacetonitrile as a positive solvent were added to dissolve the solid.Under stirring conditions, an equimolar amount of sulfuric acid wasadded to the vial at room temperature. After stirring was continued for24 hours, a solid-liquid separation was carried out to obtain crystalform II of the sulfate salt of the compound of formula I. The X-raypowder diffraction spectrum is shown in FIG. 6.

Example 7: Preparation of Crystal Form III of a Sulfate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofacetone as a positive solvent were added to dissolve the solid. Understirring conditions, an equimolar amount of sulfuric acid was added tothe vial at room temperature. After stirring was continued for 24 hours,a solid-liquid separation was carried out to obtain crystal form III ofthe sulfate salt of the compound of formula I. The X-ray powderdiffraction spectrum is shown in FIG. 7.

Example 8: Preparation of Crystal Form IV of a Sulfate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofethanol as a positive solvent were added to dissolve the solid. Understirring conditions, an equimolar amount of sulfuric acid was added tothe vial at room temperature. After stirring was continued for 24 hours,a solid-liquid separation was carried out to obtain crystal form IV ofthe sulfate salt of the compound of formula I. The X-ray powderdiffraction spectrum is shown in FIG. 8.

Example 9: Preparation of Crystal Form I of a Phosphate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofacetonitrile as a positive solvent were added to dissolve the solid.Under stirring conditions, an equimolar amount of phosphoric acid wasadded to the vial at room temperature. After stirring was continued for24 hours, a solid-liquid separation was carried out to obtain crystalform I of the phosphoric salt of the compound of formula I. The X-raypowder diffraction spectrum is shown in FIG. 9.

Example 10: Preparation of Crystal Form I of a Mesylate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofdioxane as a positive solvent were added to dissolve the solid. Understirring conditions, 2.5 μL of methanesulfonic acid were added to thevial at room temperature. After stirring was continued for 24 hours, asolid-liquid separation was carried out to obtain crystal form I of themesylate salt of the compound of formula I. The X-ray powder diffractionspectrum is shown in FIG. 10.

Example 11: Preparation of Crystal Form II of a Mesylate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofisopropanol as a positive solvent were added to dissolve the solid.Under stirring conditions, 2.5 μL of methanesulfonic acid were added tothe vial at room temperature. After stirring was continued for 24 hours,a solid-liquid separation was carried out to obtain crystal form II ofthe mesylate salt of the compound of formula I. The X-ray powderdiffraction spectrum is shown in FIG. 11.

Example 12: Preparation of Crystal Form III of a Mesylate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofdichloromethane as a positive solvent were added to dissolve the solid.Under stirring condition, 2.5 μL of methanesulfonic acid were added tothe vial at room temperature. After stirring was continued for 24 hours,a solid-liquid separation was carried out to obtain crystal form III ofthe mesylate salt of the compound of formula I. The X-ray powderdiffraction spectrum is shown in FIG. 12.

Example 13: Preparation of Crystal Form IV of a Mesylate Salt of theCompound of Formula I

About 20 mg of a mesylate salt solid of the compound of formula I wereweighed and placed in a 1.5 mL vial, and then 0.5 mL of methyltert-butyl ether was added. After stirring was continued for 24 hours, asolid-liquid separation was carried out to obtain crystal form IV of themesylate salt of the compound of formula I. The X-ray powder diffractionspectrum is shown in FIG. 13.

Example 14: Preparation of Crystal Form V of a Mesylate Salt of theCompound of Formula I

About 20 mg of a mesylate salt solid of the compound of formula I wasweighed and placed in a 1.5 mL vial, and then 0.5 mL of tetrahydrofuranwas added. After stirring was continued for 24 hours, a solid-liquidseparation was carried out to obtain crystal form V of the mesylate saltof the compound of formula I. The X-ray powder diffraction spectrum isshown in FIG. 14.

Example 15: Preparation of Crystal Form VI of a Mesylate Salt of theCompound of Formula I

About 20 mg of a mesylate salt solid of the compound of formula I wereweighed and placed in a 1.5 mL vial, and then 0.5 mL of isopropanol wasadded. After stirring was continued for 24 hours, a solid-liquidseparation was carried out to obtain crystal form VI of the mesylatesalt of the compound of formula I. The X-ray powder diffraction spectrumis shown in FIG. 15.

Example 16: Preparation of Crystal Form I of a Fumarate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofacetonitrile as a positive solvent were added to dissolve the solid.Under stirring conditions, an equimolar amount of fumaric acid was addedto the vial at room temperature. After stirring was continued for 24hours, a solid-liquid separation was carried out to obtain crystal formI of the fumaric salt of the compound of formula I. The X-ray powderdiffraction spectrum is shown in FIG. 16.

Example 17: Preparation of Crystal Form II of a Fumarate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofacetone as a positive solvent were added to dissolve the solid. Understirring conditions, an equimolar amount of fumaric acid was added tothe vial at room temperature. After stirring was continued for 24 hours,a solid-liquid separation was carried out to obtain crystal form II ofthe fumaric salt of the compound of formula I. The X-ray powderdiffraction spectrum is shown in FIG. 17.

Example 18: Preparation of Crystal Form I of a Maleate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofacetonitrile as a positive solvent were added to dissolve the solid.Under stirring conditions, an equimolar amount of maleate acid was addedto the vial at room temperature. After stirring was continued for 24hours, a solid-liquid separation was carried out to obtain crystal formI of the maleate salt of the compound of formula I. The X-ray powderdiffraction spectrum is shown in FIG. 18.

Example 19: Preparation of Crystal Form II of a Maleate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofethyl acetate as a positive solvent were added to dissolve the solid.Under stirring conditions, an equimolar amount of maleate acid was addedto the vial at room temperature. After stirring was continued for 24hours, a solid-liquid separation was carried out to obtain crystal formII of the maleate salt of the compound of formula I. The X-ray powderdiffraction spectrum is shown in FIG. 19.

Example 20: Preparation of Crystal Form III of a Maleate Salt of theCompound of Formula I

About 400 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 20 mL vial, and then 4 mL ofethyl acetate as a positive solvent were added to dissolve the solid.Under stirring conditions, an equimolar amount of maleate acid was addedto the vial at room temperature. After stirring was continued for 24hours, a solid-liquid separation was carried out to obtain crystal formIII of the maleate salt of the compound of formula I. The X-ray powderdiffraction spectrum is shown in FIG. 20.

Example 21: Preparation of Crystal Form I of an Acetate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofacetonitrile as a positive solvent were added to dissolve the solid.Under stirring conditions, an equimolar amount of acetic acid acid wasadded to the vial at room temperature. After stirring was continued for24 hours, a solid-liquid separation was carried out to obtain crystalform I of the acetic acid salt of the compound of formula I. The X-raypowder diffraction spectrum is shown in FIG. 21.

Example 22: Preparation of Crystal Form II of an Acetate Salt of theCompound of Formula I

About 20 mg of the free base solid of the compound of formula I(amorphous) were weighed and placed in a 1.5 mL vial, and then 200 μL ofethyl acetate as a positive solvent were added to dissolve the solid.Under stirring conditions, an equimolar amount of acetic acid acid wasadded to the vial at room temperature. After stirring was continued for24 hours, a solid-liquid separation was carried out to obtain crystalform II of the acetic acid salt of the compound of formula I. The X-raypowder diffraction spectrum is shown in FIG. 22.

Finally, it should be noted that the above examples are used only toillustrate the technical solution of the present invention, but are notlimited to the scope of the present invention. Although the presentinvention has been described in detail with reference to the preferredexamples, those skilled in the art would understand that the technicalsolution of the present invention can be modified or equivalently variedwithout departing from the spirit and scope of the invention, and suchmodifications and variations should be included in the claims of thepresent invention.

What is claimed is:
 1. A acid salt ofN-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide(a compound of formula I), wherein the acid salt comprises an inorganicacid salt or an organic acid salt; wherein the inorganic acid salt isselected from the group consisting of hydrochloride, sulfate,hydrobromide, hydrofluoride, hydroiodide and phosphate; wherein theorganic acid salt is selected from the group consisting of acetate,propionate, hexanoate, caprylate, fumarate, maleate, malonate,succinate, glutarate, adipate, sebacate, dichloroacetate,trichloroacetate, acetohydroxamate, salicylate, 4-aminosalicylate,benzoate, 4-acetylaminobenzoate, 4-aminobenzoate, caprate, cinnamate,citrate, aspartate, camphorate, gluconate, glucuronate, glutamate,erythorbate, lactate, aspartate, malate, mandelate, pyroglutamate,tartrate, lauryl sulfate, dibenzoyltartrate, 2,5-dihydroxybenzoate,1-hydroxy-2-naphthoate, mesylate, ethyl-1,2-disulfonate,ethanesulfonate, benzenesulfonate, 4-chlorobenzenesulfonate,p-toluenesulfonate, cyclohexylsulfamate, camphorsulfonate,1,5-naphthalenedisulfonate, naphthalene-2-sulfonate, formate,galactonate, gentisate, 2-ketoglutarate, glycolate, hippurate,isethionate, lactobionate, ascorbate, aspartate, laurate, camphorate,nicotinate, oleate, orotate, oxalate, palmitate, pamoate, stearate,thiocyanate, undecylenate, trifluoroacetate and succinate.
 2. The acidsalt of the compound of formula I according to claim 1, wherein the acidsalt polymorph is a mesylate salt polymorph, selected from the groupconsisting of crystal form I of a mesylate salt, crystal form II of amesylate salt, crystal form III of a mesylate salt, crystal form IV of amesylate salt, crystal form V of a mesylate salt, and crystal form VI ofa mesylate crystal, wherein an X-ray powder diffraction spectrum ofcrystal form I of the mesylate salt comprises peaks at diffractionangles (2θ) of 19.1±0.2°, 25.6±0.2°, 15.0±0.2° and 25.0±0.2°; wherein anX-ray powder diffraction spectrum of crystal form II of the mesylatesalt comprises peaks at diffraction angles (2θ) of 24.3±0.2°, 20.1±0.2°,11.0±0.2° and 20.6±0.2°, preferably, further comprises peaks atdiffraction angles (2θ) of 17.4±0.2°, 22.7±0.2°, 23.8±0.2°, 12.1±0.2°and 15.7±0.2°, more preferably, further comprises peaks at diffractionangles (2θ) of 8.7±0.2°, 16.7±0.2°, 15.1±0.2, 18.5±0.2°, 17.7±0.2° and6.5±0.2°; wherein an X-ray powder diffraction spectrum of crystal formIII of the mesylate salt comprises peaks at diffraction angles (2θ) of24.5±0.2°, 22.6±0.2°, 6.1±0.2° and 18.8±0.2°; wherein an X-ray powderdiffraction spectrum of crystal form IV of the mesylate salt comprisespeaks at diffraction angles (2θ) of 21.0±0.2°, 18.0±0.2°, 25.1±0.2° and13.6±0.2°; wherein an X-ray powder diffraction spectrum of crystal formV of the mesylate salt comprises peaks at diffraction angles (2θ) of24.6±0.2°, 23.3±0.2°, 14.9±0.2° and 20.1±0.2°; wherein an X-ray powderdiffraction spectrum of crystal form VI of the mesylate salt comprisespeaks at diffraction angles (2θ) of 11.7±0.2°, 19.8±0.2°, 17.2±0.2° and6.8±0.2°.
 3. The acid salt of the compound of formula I according toclaim 1, wherein the acid salt polymorph is a fumarate salt polymorph,selected from the group consisting of crystal form I of a fumarate saltand crystal form II of a fumarate salt, wherein an X-ray powderdiffraction spectrum of crystal form I of the fumarate salt comprisespeaks at diffraction angles (2θ) of 7.1±0.2°, 12.0±0.2°, 14.9±0.2° and17.1±0.2°; wherein an X-ray powder diffraction spectrum of crystal formII of the fumarate salt comprises peaks at diffraction angles (20) of6.0±0.2°, 22.7±0.2°, 25.1±0.2° and 23.3±0.2°.
 4. The acid salt of thecompound of formula I according to claim 1, wherein the acid saltpolymorph is a maleate salt, preferably selected from the groupconsisting of crystal form I of a maleate salt, crystal form II of amaleate salt and crystal form III of a maleate salt; wherein an X-raypowder diffraction spectrum of crystal form I of the maleate saltcomprises peaks at diffraction angles (2θ) of 7.9±0.2°, 24.6±0.2°,7.5±0.2° and 18.2±0.2°; wherein an X-ray powder diffraction spectrum ofcrystal form II of the maleate salt comprises peaks at diffractionangles (2θ) of 20.3±0.2°, 24.9±0.2°, 23.4±0.2° and 16.8±0.2°; wherein anX-ray powder diffraction spectrum of crystal form III of the maleatesalt comprises peaks at diffraction angles (2θ) of 21.6±0.2°, 22.4±0.2°,17.9±0.2° and 25.8±0.2°
 5. The acid salt of the compound of formula Iaccording to claim 1, wherein the acid salt polymorph is selected froman acetate salt, selected from the group consisting of crystal form I ofan acetate salt and crystal form II of an acetate salt; wherein an X-raypowder diffraction spectrum of crystal form I of the acetate saltcomprises peaks at diffraction angles (2θ) of 23.0±0.2°, 11.8±0.2°,16.3±0.2° and 7.4±0.2°; wherein an X-ray powder diffraction spectrum ofcrystal form II of the acetate salt comprises peaks at diffractionangles (2θ) of 8.4±0.2°, 19.9±0.2°, 23.0±0.2° and 24.8±0.2°.
 6. A methodfor preparing the acid salt of the compound of formula I according toclaim 1, comprises the following step of: preparing the acid salt of thecompound of formula I as follows: dissolving or dispersing the free baseof the compound in an aqueous solvent or a suitable organic solvent, andthen adding a liquid or solid or solution of inorganic acid or organicacid to the above system to prepare the acid salt of the compound offormula I; or, adding the free base solid to an acid solution to preparethe acid salt of the compound of formula I.
 7. A method for preparingthe acid salt of the compound of formula I according to claim 6, whereinthe organic solvent is selected from the group consisting of methanol,ethanol, isopropanol, acetonitrile, acetone, ethyl acetate, isopropylacetate, toluene, n-butanol, cyclohexane, dichloromethane,dimethylformamide, dimethylacetamide, dimethyl sulfoxide, dioxane, ethylether, n-heptane, n-hexane, methyl ethyl ketone, isooctane, pentane,dipropanol, tetrahydrofuran, dimethyl tetrahydrofuran, trichloroethane,and dimethylbenzene, or a mixture thereof.
 8. A pharmaceuticalcomposition comprising a therapeutically effective amount of the acidsalt of the compound of formula I according to any one of claims 1, anda pharmaceutically acceptable carrier.
 9. The acid salt of the compoundof formula I according to claim 1, the acid salt is selected from thegroup consisting of mesylate, fumurate, maleate, and acetate.
 10. Theacid salt of the compound of formula I according to claim 1, wherein theacid salt is mesylate.
 11. A method for treating a disease mediated bythe activity of an EGFR mutant or the activity of a mutant activated byexon 19 deletion in a subject, the method comprising administering tothe subject the pharmaceutical composition according to claim
 8. 12. Themethod according to claim 11, wherein the EGFR mutant is selected fromthe group consisting of EGFR-L858R mutant and EGFR-T790M mutant.
 13. Amethod for treating a cancer in a subject, the method comprisingadministering to the subject the pharmaceutical composition according toclaim 8, wherein the cancer is selected from the group consisting ofovarian cancer, cervical cancer, colorectal cancer, breast cancer,pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer,leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer,hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor(GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renalcancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML),multiple myeloma, melanoma, mesothelioma, and non-small cell lungcancer.
 14. The method according to claim 13, wherein the cancer isnon-small cell lung cancer.
 15. The acid salt of the compound of formulaI according to claim 1, wherein the acid salt of the compound of formulaI is crystal form.